Numerous acquired and inherited pathologic conditions are associated with chromosome specific translocations or rearrangements. Chromosome 22, although quite small, is over involved in such non-random chromosomal abnormalities. It is associated with seven distinct malignancies and three constitutional syndromes of clinical significance. Developments in molecular biology, especially the ability to analyze large DNA fragments, have revolutionized the study of chromosomal rearrangements. One of the aims of this proposal is to prepare a long range physical map of 22q11 using this new technology. Our mapping strategy is designed to permit detection and analysis of any rearrangement within this region. This proposal, however, has a particular focus on the t(11;22) of Ewing's sarcoma, the t(11;22) of the Supernumerary der(22)t(11;22) syndrome, and the monosomy of 22q11 seen in association with DiGeorge syndrome. Completion of the long range map should lead to improved diagnosis for Ewing's sarcoma and will open new areas of investigation regarding the basic mechanisms which permit or promote recombination at a chromosomal and molecular level. Comparisons between physical and genetic maps will provide vital information regarding recombinational "hot spots" in the human genome. Finally, the identification of specific genes involved in these non-random chromosomal abnormalities should greatly increase our understanding of the pathogenesis both of Ewing's tumors and of the developmental disorders associated with chromosome 22. The studies we propose represent a logical extension of our previous four years of work. They will rely on somatic cell genetic, molecular genetic and cytogenetic techniques. The small size and numerous rearrangements of chromosome 22 make it an excellent model system in which to examine issues related to genomic organization, chromosomal rearrangement and their role in human disease. Our multi-disciplinary approach should accelerate progress toward achieving a map of chromosome 22 and will assist in elucidating the biological significance of its numerous disease-related abnormalities.